Peptide drugs: a new direction in cancer immunotherapy

Cancer immunotherapy has emerged as a promising approach in cancer treatment and is considered a major advancement after surgical interventions, radiotherapy, chemotherapy, and targeted therapy. The clinical use of immunotherapeutic drugs, particularly antibody-based drugs that target immune checkpoints, has notably increased~1.

Vitamin D,selenium,and antidiabetic drugs in the treatment of type 2 diabetes mellitus with Hashimoto's thyroiditis

BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.

Development of small molecule drugs targeting immune checkpoints

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

Systematic review and network meta-analysis of different nonsteroidal anti-inflammatory drugs for juvenile idiopathic arthritis

BACKGROUND Various non-steroidal anti-inflammatory drugs(NSAIDs)have been used for juvenile idiopathic arthritis(JIA).However,the optimal method for JIA has not yet been developed.AIM To perform a systematic review and network meta-analysis to determine the optimal instructions.METHODS We searched for randomized controlled trials(RCTs)from PubMed,EMBASE,Google Scholar,CNKI,and Wanfang without restriction for publication date or language at August,2023.Any RCTs that comparing the effectiveness of NSAIDs with each other or placebo for JIA were included in this network meta-analysis.The surface under the cumulative ranking curve(SUCRA)analysis was used to rank the treatments.P value less than 0.05 was identified as statistically significant.RESULTS We included 8 RCTs(1127 patients)comparing 8 different instructions including meloxicam(0.125 qd and 0.250 qd),Celecoxib(3 mg/kg bid and 6 mg/kg bid),piroxicam,Naproxen(5.0 mg/kg/d,7.5 mg/kg/d and 12.5 mg/kg/d),inuprofen(30-40 mg/kg/d),Aspirin(60-80 mg/kg/d,75 mg/kg/d,and 55 mg/kg/d),Tolmetin(15 mg/kg/d),Rofecoxib,and placebo.There were no significant differences between any two NSAIDs regarding ACR Pedi 30 response.The SUCRA shows that celecoxib(6 mg/kg bid)ranked first(SUCRA,88.9%),rofecoxib ranked second(SUCRA,68.1%),Celecoxib(3 mg/kg bid)ranked third(SUCRA,51.0%).There were no significant differences between any two NSAIDs regarding adverse events.The SUCRA shows that placebo ranked first(SUCRA,88.2%),piroxicam ranked second(SUCRA,60.5%),rofecoxib(0.6 mg/kg qd)ranked third(SUCRA,56.1%),meloxicam(0.125 mg/kg qd)ranked fourth(SUCRA,56.1%),and rofecoxib(0.3 mg/kg qd)ranked fifth(SUCRA,56.1%).CONCLUSION In summary,celecoxib(6 mg/kg bid)was found to be the most effective NSAID for treating JIA.Rofecoxib,piroxicam,and meloxicam may be safer options,but further research is needed to confirm these findings in larger trials with higher quality studies.

Bacterial Exofactors Modulate Biofilm Growth and Resistivity to Antimicrobial Drugs

Some bacteria have the ability to co-exist, proliferate and survive in a multicellular community, biofilm. Each participating bacteria can form its colonies and encases itself by a self-produced insoluble extracellular matrix substance (EPS). Microcolonies within biofilm are held together by interactions and bonding of the substances present in the EPS with their separation from the water channels. Similar to insoluble EPS, bacterial microcolonies release soluble exofactors that have direct impacts on the survivability, growth and antibacterial resistivity of other microcolonies made of single- or multi-species bacteria in the same biofilm. How the exofactors of microcolonies of one-type bacteria impact on microcolonies of other-type bacteria is still unclear. We studied about the role of exofactors released from Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, which are common biofilm-forming pathogenic bacteria. Exofactors facilitate to transform the microenvironment where bacteria can acquire alternative lifestyle with a long survival period and resistivity to certain antimicrobial drugs.

Practice of Perioperative Rational Use of Antibacterial Drugs Based on Drug Pathway

[Objectives]To establish a new management model for rational use of perioperative antibacterial drugs in surgical departments.[Methods]Based on evidence-based medicine,the department s drug pathway was formulated,and the new mode of rational drug use control was established by using fine pharmaceutical technology intervention,and the intervention effect was evaluated by the intensity of antibacterial drug use,per capita drug costs and the proportion of drugs.[Results]After adopting drug pathway in departments,the intensity of antibacterial drug use,per capita drug costs and the proportion of drugs decreased significantly,and the effect of rational drug use control was remarkable.[Conclusions]The drug pathway provides a new management and control mode for the rational use of perioperative antibacterial drugs in surgical departments of hospitals.Thus,it is worthy of popularization and application.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

Alcohol and illicit drugs:prevalence of alcohol and illicit drug use and their predictors in young people from Argentina,Bulgaria,Chile and Romania

Background:Alcohol and illicit drugs(AID)continue to be a major global health concern.Although preventable,AID is linked to millions of deaths annually worldwide.The situation is particularly grave for young people,with AID being a major direct risk factor for disability-adjusted youth life-years lost and death.It further contributes to assaults,road crashes,accidental poisoning,and suicide,leading to long-term issues and public health concerns.Objective:This study aimed at disclosing current AID prevalence data for Argentinian,Bulgarian,Chilean and Romanian youth.It shed light on the predictors of AID in young people from those countries.Method:The study used an online survey to gather data from people aged 18 to 25(n=1,297).The survey was underpinned by the theory of planned behaviour(TPB).Predictors were investigated separately for drinking alcohol and using illicit drugs.Results:Our data revealed that across the four target countries,49%to 90%of the participants drank alcohol,and 8%to 35%used illicit drugs in the past three months.Between 20%and 91%of them intended to drink,and between 8%and 31%intended to use illicit drugs in the following three months.Our TPB model predicted statistically significant(P<0.001)amounts of variance in drinking alcohol(between 61%and 72%)and using illicit drugs(between 20.3%and 74.4%).Intention was consistent in significantly predicting both behaviours.Evidence around the predictive validity of self-efficacy,age and gender was mixed across the investigated countries.Conclusion:This research provided an update on the scarce AID epidemiological data.It also supplied evidence about what theoretically-informed measures might be useful targets of interventions in the case of Argentina,Bulgaria,Chile and Romania.This new knowledge of understanding substance abuse determinants and prevalence may help researchers and practitioners better meet young people's health prevention needs.

Nonsteroidal anti-inflammatory drugs before endoscopic ultrasound guided tissue acquisition to reduce the incidence of post procedural pancreatitis

Endoscopic ultrasound(EUS)with fine needle aspiration or fine needle biopsy is the gold standard for sampling tissue to diagnose pancreatic cancer and auto-immune pancreatitis or to analyze cyst fluid.The most common reported adverse event of fine needle aspiration and/or fine needle biopsy is acute pancreatitis,which is likely induced by the same pathophysiological mechanisms as after en-doscopic retrograde cholangiopancreatography(ERCP).According to the current European Society of Gastrointestinal Endoscopy guideline,nonsteroidal anti-inflammatory drugs are administered prior to ERCP as a scientifically proven treatment to reduce post-ERCP pancreatitis incidence rate.A single suppository of diclofenac or indomethacin prior to EUS guided tissue acquisition(TA)is harm-less in healthy adults.Since it is associated with low costs and,most important,may prevent a dreadsome complication,we strongly recommend the adminis-tration of 100 mg diclofenac rectally prior to EUS-TA.We will explain this recom-mendation in more detail in this review as well as the risk and pathophysiology of post-EUS TA pancreatitis.

Keep in mind sex differences when prescribing psychotropic drugs

Women represent the majority of patients with psychiatric diagnoses and also the largest users of psychotropic drugs.There are inevitable differences in efficacy,side effects and long-term treatment response between men and women.Psychopharmacological research needs to develop adequately powered animal and human trials aimed to consider pharmacokinetics and pharmacodynamics of central nervous system drugs in both male and female subjects.Healthcare professionals have the responsibility to prescribe sex-specific psychopharmacotherapies with a priority to differentiate between men and women in order to minimize adverse drugs reactions,to maximize therapeutic effectiveness and to provide personalized management of care.

Association between glucose-lowering drugs and circulating insulin antibodies induced by insulin therapy in patients with type 2 diabetes

BACKGROUND Insulin antibodies(IAs)affect blood glucose control in patients receiving insulin therapy.AIM To investigate the relationship between different hypoglycemic treatments and IAs in patients with type 2 diabetes mellitus(T2DM).METHODS This cross-sectional,retrospective study included 1863 patients with T2DM who were receiving exogenous insulin therapy.All patients received stable antidiabetic therapy in the last 3 months and IA levels were measured using an iodine-125 array.RESULTS A total of 1863 patients were enrolled.There were 902(48.4%)patients who had positive IAs(IA level>5%),with a mean IA level of 11.06%(10.39%-11.72%).IA levels were positively correlated with high fasting blood glucose(odds ratio=1.069,P<0.001).The proportion of positive IAs was lowest in patients using glargine only(31.9%)and highest in patients using human insulin only(70.3%),P<0.001.The IA levels in patients using sulfonylureas/glinides(8.3%),metformin(9.6%),and dipeptidyl peptidase-4 inhibitors(8.2%)were all lower than in patients without these drugs(all P<0.05).CONCLUSION Nearly half of patients on insulin therapy have positive IA antibodies,and IA antibody levels are associated with blood glucose control.Insulin glargine and a combination of oral glucose-lowering drugs were correlated with lower IA levels.

An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

Antibacterial resistance is a global health threat that requires further concrete action on the part of all countries.In this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and developed.Although several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in China.In this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since 2019.Information was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other reviews.As of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and updated.Among them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in phase-1.Most of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial protein.Overall,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in China.Hopefully,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

Research Progress of Atomizers and Drugs Used in Atomization Therapy

At present,the commonly used treatment methods for chronic respiratory diseases are drug,oxygen,interventional and atomization therapy.Atomization therapy is the most widely used because of its characteristics of fast effect,high local drug concentration,less drug dosage,convenient application and few systemic adverse reactions.In this paper,the mechanism,characteristics,commonly used drugs and clinical application of atomization therapy are discussed.

Recognition and quality mapping of traditional herbal drugs:way forward towards artificial intelligence

The use of traditional herbal drugs derived from natural sources is on the rise due to their minimal side effects and numerous health benefits.However,a major limitation is the lack of standardized knowledge for identifying and mapping the quality of these herbal medicines.This article aims to provide practical insights into the application of artificial intelligence for quality-based commercialization of raw herbal drugs.It focuses on feature extraction methods,image processing techniques,and the preparation of herbal images for compatibility with machine learning models.The article discusses commonly used image processing tools such as normalization,slicing,cropping,and augmentation to prepare images for artificial intelligence-based models.It also provides an overview of global herbal image databases and the models employed for herbal plant/drug identification.Readers will gain a comprehensive understanding of the potential application of various machine learning models,including artificial neural networks and convolutional neural networks.The article delves into suitable validation parameters like true positive rates,accuracy,precision,and more for the development of artificial intelligence-based identification and authentication techniques for herbal drugs.This article offers valuable insights and a conclusive platform for the further exploration of artificial intelligence in the field of herbal drugs,paving the way for smarter identification and authentication methods.

Non-steroidal anti-inflammatory drugs in postoperative hand fracture management:Do they positively or negatively impact recovery?

This editorial explores the impact of non-steroidal anti-inflammatory drugs(NSAIDs)on postoperative recovery in hand fracture patients,amidst shifting pain management strategies away from opioids due to their adverse effects.With hand fractures being significantly common and postoperative pain management crucial for recovery,the potential of NSAIDs offers a non-addictive pain control alternative.However,the controversy over NSAIDs'effects on bone healing—stemming from their Cyclooxygenase-2 inhibition and associated risks of fracture non-union or delayed union—necessitates further investigation.Despite a comprehensive literature search,the study finds a lack of specific research on NSAIDs in postoperative hand fracture management,highlighting an urgent need for future studies to balance their benefits against possible risks.

Research Progress on the Bone Metastasis Mechanism of Prostate Cancer and Bone-Targeted Drugs

Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.

Research progress of local characteristic drugs for treatment of rheumatoid arthritis in Xinjiang

Rheumatoid arthritis(RA)is a systemic autoimmune disease characterized by synovitis.This disease tends to recur,persist,and is difficult to cure.The pathogenesis of RA is complex.Currently,the commonly used treatments for RA—non-steroidal anti-inflammatory drugs(NSAIDs),disease-modifying anti-rheumatic drugs(DMARDs),glucocorticoids,and immunosuppressants—have notable side effects with long-term use and may be ineffective for some patients.Therefore,it is crucial to find drugs with limited side effects and significant curative effects.Xinjiang's local characteristic drugs have a long history,abundant resources,and are known for their safety and effectiveness in treating RA.In recent years,many studies have reported on the mechanisms of action and therapeutic effects of Xinjiang's local characteristic drugs on RA.This article reviews the pathogenesis of RA,as well as the research progress and treatment characteristics of Xinjiang-featured drugs.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

The Level of Knowledge, Behaviors, and Attitudes on Rational Use of Drugs of Patients Who Applied to the Family Health Center in Istanbul, Türkiye: A Cross-Sectional Study

Background: This study, it was aimed to determine the level of knowledge, attitudes, and behaviors of patients who applied to a family health center about the rational use of drugs. Irrational use of drugs is a major problem worldwide. WHO reports that half of the patients do not use their drugs correctly. Methods: This cross-sectional study was conducted between 1 October 2017 and 30 November 2018 at Istanbul Fatih Family Health Center No 7. The sample size was determined as 301 people selected by systematic sampling method from patients aged 18 and older. Results: The mean age of the participants was 53.8% ± 16.8%, 59.8% were female, 62.5% were married, and 52.5% were primary school graduates. 63.9% of the participants knew the names of the drugs they used, and 79.9% of them knew the indication for use. 89% of individuals check the expiry date of the drugs before using them, and 83.1% read the drug prospectus. 84% of the participants support the prohibition of using over-the-counter drugs. Conclusion: The level of knowledge of the participants about the rational use of drugs is above the societal average. However, some issues need more awareness. The high level of rational use of drugs awareness of physicians and pharmacists will also strengthen the rational use of drugs and indirectly increase the awareness of the public.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).